It is firmly established that states of energy deficiency, such as fasting, anorexia nervosa, cachexia, bulimia, lactation and exercise-induced amenorrhea, as well as states of energy overabundance, such as obesity, are both associated with disruptions in fertility. These studies focus on states of negative energy balance that are associated with a suppression of reproductive function. The identity of the specific metabolic signals or afferent neural pathways that convey information about energy balance to gonadotropin-releasing hormone (GnRH) neurons, the central hypothalamic system regulating reproduction, remains elusive. Key to elucidating this link is an understanding of the regulation of kisspeptin neurons, the primary gatekeepers in controlling GnRH neurons. Our studies use two models of negative energy balance, lactation and caloric restriction, and have shown that kisspeptin signaling is greatly suppressed during these states. A key hypothesis of this proposal is that suppression of kisspeptin signaling is the primary factor in the inhibition of GnRH during states of negative energy balance. Although it is a widely held view that hypoleptinemia is the critical factor linking energy balance and suppressed GnRH, our recent studies demonstrate that restoring leptin to normal physiological levels does not reverse the inhibition of kisspeptin r GnRH in either lactation or caloric restriction. Thus, hypoleptinemia does not appear to be the primary metabolic factor responsible for the suppression of reproductive function. The proposed studies focus on new systems for integrating metabolic signals. Our hypothesis is that brainstem systems, such as glucose sensing catecholaminergic neurons, may be the site where information about metabolic signals is relayed to hypothalamic systems regulating GnRH neurons. This proposal focuses on two hypotheses: 1) Suppression of kisspeptin signaling at the site of GnRH cell bodies and at nerve fibers and terminals are primary components in the inhibition of basal GnRH secretion during states of negative energy balance, and 2) Brainstem systems serve as a site of integration of metabolic signals and provide the afferent signals that are responsible for the suppression of kisspeptin and GnRH during negative energy balance. These studies will use transgenic and wild-type rats and mice to identify mechanisms by which a decrease in kisspeptin tone coupled with increased inhibitory input to GnRH cell bodies results in a decrease in GnRH neuronal excitability, and will explore the roles of kisspeptin and neurokinin B in regulating GnRH release from nerve terminals. Studies will also establish the functional connectivity of afferent neural input that suppresses kisspeptin neurons. We propose that once the inhibitory input to kisspeptin neurons is identified, blocking the input will not onl restore kisspeptin but also reverse the inhibition on GnRH. Elucidating the specific links between energy balance and reproductive function has been a long-term goal for the past several decades. These studies will identify new pathways that regulate kisspeptin neurons that in turn control GnRH neurons and could lead to new treatments for restoring fertility or for new contraceptive agents that inhibit fertility. PUBLIC HEALTH RELEVANCE: An imbalance in energy stores is associated with an inhibition of reproductive function and disruptions in fertility. However, the specific metabolic signals and the integration sites in the brain that link energy balance and reproductive function are poorly understood. These studies will identify key mechanisms and regulatory pathways for transmitting information about energy balance to neural systems regulating reproductive function.